Dispersions of drugs or other biological agents in nonaqueous, typically polymeric, matrices are commonly used as reservoirs for delivery devices, representative devices being disclosed U.S. Pat. Nos. 3,598,122 and 3,598,123 to Zaffaroni et al, 4,031,894 to Urquhart et al and 4,201,211 to Chandrasekaran et al which patents are incorporated herein by reference. For convenience the term "drug" will be hereafter used in its broadest sense to include any biologically active agent which is delivered to its environment of use to produce a biological effect. The drugs may be in solid form as for example in Chandrasekaran et al or in the form of a liquid dispersion as in Urquhart et al. It is with respect to such liquid dispersions that this invention relates.
Although this invention will be described hereafter specifically with respect to scopolamine delivery devices, it should be recognized that it is applicable to dispersions of any other drug which is in a liquid state at ambient temperatures and forms a crystalline hydrate upon exposure to water. Such drugs as nicotine, secoverine and benztropine, for example, may, to the extent they form crystalline hydrates, be treated in a manner similar to the methods by which dispersions of scopolamine base are treated according to this invention.
Transdermal delivery devices for the administration of scopolamine of the type disclosed by Urquhart et al are used extensively for the prevention of motion sickness. The product is manufactured as described in the patent by solvent casting of chloroform solutions of scopolamine base in polyisobutene (PIB) and mineral oil (MO) onto impermeable webs to form drug reservoir and adhesive films. Upon evaporation of the chloroform, a dispersion of liquid scopolamine base in the PIB/MO matrix is formed. The drug reservoir and adhesive films are then laminated to opposite sides of a release rate controlling membrane, formed from a mineral oil impregnated microporous film, to produce a multilaminate comprising a removable release liner lamina, an adhesive lamina, a rate controlling membrane lamina, a drug reservoir lamina and an impermeable backing lamina. The multilaminate is then die cut into individual systems and packaged in individual heat sealed foil pouches.
The manufacture of the product in this manner was carried out for approximately five years with no indication of the formation of any crystals of scopolamine hydrate in either the drug reservoir or the adhesive. After that time, small crystals of scopolamine hydrate were observed, but this did not present a problem because the release rate of the drug from the device was not affected by the presence of the small number of small crystals then occurring.
Approximately two years later, larger numbers of rapidly propagating crystals were observed, primarily in the drug reservoir, with a lower incidence being observed in the contact adhesive layer which contained a lower concentration of scopolamine base. At that time, the size of the crystals and their frequency of occurrence had increased to the point where they produced a significant adverse effect on the release rate of scopolamine from the device. Thereafter, every lot manufactured developed unacceptably high crystal size and frequency and commercial production had to be halted until the problem could be solved.
The individual laminate films and the multilaminate films exhibited crystallization at a much lower frequency. After the multilaminate film was fed through the die-cutting machine for the formation of the individual transdermal delivery units, crystallization began around the edges of the cut product and crystalline growth thereafter propagated rapidly throughout the mass of the reservoir and in some cases the adhesive layer. Visually observable crystals were not necessarily apparent immediately after the cutting step; instead they would typically develop over a period of days. Microscopic examination detected crystals at an earlier stage, suggesting that submicroscopic nucleation sites are present at an even earlier time.
It should be noted that the above described crystallization phenomena occurred without any significant change in the manufacturing facilities, equipment or processes and, once it had occurred, it never ceased occurring. Various attempts to eliminate the problem were tried over several months, all to no avail. For example, the drug reservoir laminate, adhesive laminate an the multilaminate film were heated overnight with no observable effect. The casting solutions were similarly heated and allowed to stand for extended periods also with no effect. Because crystallization seemed to appear after the step in which the multilaminate film is cut into individual devices, cutting and packaging the systems under dry nitrogen was instituted but crystals still appeared.
Attempts were also made to remove water from other stages of the manufacturing process. The scopolamine base is produced from an aqueous solution of scopolamine hydrobromide by titration to a basic pH with sodium hydroxide and extracting the base so formed with chloroform. The chloroform solution of the scopolamine base is then admixed with the PIB and MO as described in the aforesaid Urquhart et al patent to provide the appropriate casting solutions.
To reduce the amount of residual water in the chloroform solution of the scopolamine base, the solution was dried with drying agents such as anhydrous sodium sulfate and magnesium sulfate. Crystallization still occurred. The chloroform solution was exposed to a molecular sieve material in order to remove residual water. Crystallization still occurred. Azeotropic distillation of the chloroform solution was attempted, again to no avail even though the water content was significantly reduced.
Another approach considered was to allow the casting solutions to age for up to two weeks prior to casting and to heat the solutions prior to casting up to 60.degree. C. overnight. This too was ineffective in preventing the occurrence of the crystals.
Against this background, it was therefore totally unexpected when the process developed by the applicants was tested and found successful for the prevention of the formation of the scopolamine hydrate crystals.
It is accordingly an object of this invention to prevent the formation of crystalline hydrate in a dispersion of a hydratable liquid in a nonaqueous matrix.
It is another object of this invention to prevent formation of crystals of scopolamine hydrate in dispersions of scopolamine base in a nonaqueous matrix.
It is another object of this invention to manufacture transdermal therapeutic systems for the controlled delivery of scopolamine base which are free from crystals of scopolamine hydrate.
These and other objects of this invention will be readily apparent from the following description of the invention.